Methods for dose initiation of aripiprazole treatments

ABSTRACT

The present disclosure is directed to a method of dose initiation for an aripiprazole treatment to a patient in need thereof; the patient is administered two, separate 100 to 500 mg injections of an aripiprazole intramuscular (IM) depot formulation at separate gluteal and/or deltoid injection sites, and a single dose of oral aripiprazole. The administration occurs on a first day of the treatment.

TECHNICAL FIELD

The present application claims priority to U.S. Provisional ApplicationNo. 63/003,544, filed Apr. 1, 2020; the content of this application isincorporated by reference herein in its entirety.

BACKGROUND ART

Aripiprazole, a partial agonist at the dopamine (D2) and serotonin5-HT1A receptors, and an antagonist at serotonin 5-HT2A receptors, is anatypical antipsychotic that has demonstrated efficacy in clinical trialsfor the treatment of schizophrenia and bipolar I disorder in adults.Abilify Maintena®, the intramuscular (IM) depot formulation ofaripiprazole, is a prolonged-release suspension for injection. It isapproved in many countries for the maintenance treatment ofschizophrenia in adult patients stabilized with oral aripiprazole.

SUMMARY OF INVENTION Technical Problem

Aripiprazole once monthly is a long acting IM injectable formulation ofaripiprazole indicated for maintenance treatment of schizophrenia andbipolar I disorder in adult patients stabilized on oral aripiprazole. Inthe currently approved label for Abilify Maintena®, a first dose isadministered with concomitant oral aripiprazole (10 mg to 20 mg) forfourteen consecutive days to adult patients stabilized with oralaripiprazole. In patient populations considered to be at potential riskfor adherence-related relapse or suboptimal treatment outcomes (e.g.,long acting injectable (LAI) patient population), achieving therapeuticplasma concentrations may offer a treatment advantage.

Solution to Problem

To provide an additional option for this initiation stage, atwo-injection start initiation regimen comprising two, separateadministrations of aripiprazole once-monthly at separate gluteal and/ordeltoid injection sites with a single oral dose of aripiprazole on thefirst day of treatment is provided based on population pharmacokinetic(popPK) modeling and simulation. For example, the present disclosure isdirected to an alternative initiation regimen of two, separateadministrations of an aripiprazole intramuscular (IM) depot formulation,such as Abilify Maintena®, together with a shorter oral overlap.Simulations of the alternative initiation regimen of two injections ofan aripiprazole intramuscular (IM) depot formulation at separate glutealand/or deltoid injection sites together with a single oral aripiprazoleon the first day of treatment is shown to be sufficient and thealternative initiation regimen may be an additional option forinitiation of Abilify Maintena®.

In some aspects, the present disclosure is directed to a method of doseinitiation for an aripiprazole treatment to a patient in need thereofcomprising: administering two, separate injections of an aripiprazoleintramuscular (IM) depot formulation, wherein each injection comprisesfrom about 10 mg to about 500 mg of aripiprazole to the patient atseparate gluteal and/or deltoid injection sites, and a single dose oforal aripiprazole, wherein the step of administering occurs on a firstday of the treatment.

In additional aspects, each of the two, separate injections comprisesabout 400 mg of aripiprazole. Additionally, the methods of the presentdisclosure further comprise after the first day of treatment,administering a single monthly, maintenance injection of thearipiprazole IM depot formulation. For example, in other aspects, thesingle monthly, maintenance injection is chosen from about 300 mg andabout 400 mg of aripiprazole in the aripiprazole IM depot formulation.In further aspects, when the patient is a CYP2D6 poor metabolizer or istaking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors for greaterthan 14 days, the single monthly, maintenance injection is chosen from160 mg and 200 mg of aripiprazole in the aripiprazole IM depotformulation.

In further aspects, the two, separate injections of the aripiprazole IMdepot formulation are administered at separate gluteal injection sitesof the patient. Additionally, the two, separate injections of thearipiprazole IM depot formulation are administered at a glutealinjection site and a deltoid injection site of the patient. Further forexample, the two, separate injections of the aripiprazole IM depotformulation are administered at separate deltoid injection sites of thepatient.

In aspects of the present disclosure, the patient has schizophrenia. Inother aspects, the patient has bipolar 1 disorder.

In some further aspects, the single dose of oral aripiprazole rangesfrom about 2 mg to about 30 mg of aripiprazole. For example, the singledose of oral aripiprazole ranges from about 10 mg to about 30 mg.Additionally, for example, the single dose of oral aripiprazole is 20mg. And, in some further aspects, the single dose of oral aripiprazoleis 10 mg.

In some further aspects, when the patient is a CY2D6 poor metabolizer,each of the two, separate injections comprises about 300 mg ofaripiprazole and the single dose of oral aripiprazole is about 20 mg.

In some further aspects, the present disclosure is directed to anaripiprazole intramuscular (IM) depot formulation comprising from about10 mg to about 500 mg of aripiprazole, for use in administering two,separate injections of the aripiprazole intramuscular (IM) depotformulation to a patient in need thereof at an injection site chosenfrom a gluteal site, a deltoid site, and combinations thereof, incombination with a single dose of oral aripiprazole, wherein the step ofadministering occurs on a first day of the treatment.

In some further aspects, the present disclosure is directed toaripiprazole or a salt thereof for use in the treatment of schizophreniaor bipolar I disorder, wherein aripiprazole or a salt thereof is to beadministered to a patient in need thereof by any one of the methods ofdose initiation for an aripiprazole treatment of the present disclosure.Additionally, the present disclosure also provides use of aripiprazoleor a salt thereof in the manufacture of a medicament, whereinaripiprazole or a salt thereof is to be administered to a patient inneed thereof by any one of the methods of dose initiation for anaripiprazole treatment of the present disclosure.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a diagram of the structural model describing aripiprazole PKfollowing oral administration and IM injection in gluteal and deltoidmuscles.

FIGS. 2A-2D are diagrams of prediction corrected visual predictive checkof the final combined population pharmacokinetic (popPK) model.

FIGS. 3A-3C is a table of the purpose and description of thesimulations.

FIGS. 4A-4D are diagrams of simulated median (5^(th)-95^(th) percentile)aripiprazole concentration time profile following the current oralternative initiation regimen, followed by 400 mg intramuscular depotdose every 28 days. The shades represent the 5^(th)-95^(th) percentiles.

FIGS. 5A and 5B are diagrams of simulated median, 5^(th), 25^(th) to75^(th), and 95^(th) percentiles of pharmacokinetic profiles followingadministration of the current or alternative initiation regimen tosubjects already stabilized on 20 mg oral aripiprazole. The shades anddashed lines represent the 5^(th), 25^(th)-75^(th), and 95^(th)percentiles, respectively.

FIGS. 6A and 6B are diagrams of simulated median aripiprazoleconcentration time profiles boxplots of C_(max) following AbilityMaintena® initiation regimens to extensive and poor CYP2D6 metabolizers.The boxplot shows 5^(th), 25^(th), median, 75^(th), and 95^(th)percentiles of C_(max).

FIGS. 7A and 7B are diagrams of simulated median aripiprazoleconcentration time profiles and boxplots of C_(max) following AbilityMaintena® initiation regimens to extensive and poor metabolizers alreadystabilized on oral aripiprazole. The boxplot shows 5^(th), 25^(th),median, 75^(th), and 95^(th) percentiles of C_(max).

FIGS. 8A-8D are diagrams of simulated median pharmacokinetic profilesfollowing initiation and re-initiation with current or alternativeinitiation regimen 5 weeks after the previous intramuscular depot dose.

FIGS. 9A-9D are diagrams of simulated median pharmacokinetic profilesfollowing initiation and re-initiation with the current or alternativeinitiation regimen 6 weeks after the previous intramuscular depot dose.

FIG. 10 illustrates simulated and observed aripiprazole concentrationsfollowing oral and gluteal intramuscular depot administration ofaripiprazole in support of the definition of the therapeutic window.

FIG. 11 is a diagram of composition aripiprazole plasma concentrationtime profiles following administration of a single dose of 780 mg (N=18)or 1200 mg (N=13) aripiprazole long acting injectable and mean plasmaconcentration following administration of a single dose of 400 mgAbilify Maintena® to the gluteal muscle of subjects with schizophrenia.The shaded region represents model predicted 5^(th)-95^(th) percentileof PK profile following an initiation regimen of 20 mg oral+2×400 mg IMMaintena® to gluteal site.

FIG. 12 diagrams mean (SD) aripiprazole plasma concentration timeprofiles following administration of a single dose of 780 mg (N=18) or1200 mg (N=13) aripiprazole 2M long acting injectable ready to use tothe gluteal muscle of subjects with schizophrenia.

FIG. 13 illustrates observed aripiprazole plasma concentrations by weekafter first intramuscular depot injection. The box represents plasmaconcentrations exceeding 534 ng/mL during 2 weeks of 10-20 oral overlapafter first IM injection.

DESCRIPTION OF EMBODIMENTS

As used herein, “a” or “an” entity refers to one or more of that entity,e.g., “a compound” refers to one or more compounds or at least onecompound unless stated otherwise. As such, the terms “a” (or “an”), “oneor more”, and “at least one” are used interchangeably herein.

As used herein, the term “about” means approximately, in the region of,roughly, or around. When the term “about” is used in conjunction with anumerical range, it modifies that range by extending the boundariesabove and below the numerical values set forth. In general, the term“about” is used herein to modify a numerical value above and below thestated value by a variance of 5%.

As used herein, the term “treat,” “treating,” or “treatment,” when usedin connection with a disorder or condition, includes any effect, e.g.,lessening, reducing, modulating, ameliorating, or eliminating, thatresults in the improvement of the disorder or condition. Improvements inor lessening the severity of any symptom of the disorder or conditioncan be readily assessed according to standard methods and techniquesknown in the art. In some embodiments, the presently disclosed methodsor depot formulations can be used to treat schizophrenia and bipolar Idisorder, as maintenance monotherapy. In further embodiments, thepresently disclosed methods or depot formulations can be used to treatschizophrenia, acute treatment of manic and mixed episodes associatedwith Bipolar I disorder, major depressive disorder (MDD), irritabilitywith Autistic Disorder, and Tourette's disorder.

As used herein, a “mammal” refers to domesticated animals (e.g., dogs,cats, and horses) and humans. In some embodiments, the mammal is ahuman.

Embodiments

Without limitation, some embodiments of the disclosure include:

1. A method of dose initiation for an aripiprazole treatment to apatient in need thereof comprising:

-   -   administering two, separate injections of an aripiprazole        intramuscular (IM) depot formulation, wherein each injection        comprises from about 10 mg to about 500 mg of aripiprazole to        the patient at separate gluteal and/or deltoid injection sites,        and a single dose of oral aripiprazole, wherein the step of        administering occurs on a first day of the treatment.

2. The method according to embodiment 1, wherein each of the two,separate injections comprises 400 mg of aripiprazole.

3. The method according to embodiment 1 or 2, further comprising afterthe first day of treatment, administering a single monthly, maintenanceinjection of the aripiprazole IM depot formulation.

4. The method according to embodiment 3, wherein the single monthly,maintenance injection is chosen from about 300 mg and about 400 mg ofthe aripiprazole IM depot formulation.

5. The method according to embodiment 3, wherein when the patient is aCYP2D6 poor metabolizer or is taking concomitant CYP3A4 inhibitors orCYP2D6 inhibitors for greater than 14 days, the single monthly,maintenance injection is chosen from 160 mg and 200 mg of thearipiprazole IM depot formulation.

6. The method according to any one of embodiments 1 to 5, wherein thetwo, separate injections of the aripiprazole IM depot formulation areadministered at separate gluteal injection sites of the patient.

7. The method according to any one of embodiments 1 to 5, wherein thetwo, separate injections of the aripiprazole IM depot formulation areadministered at gluteal and deltoid injection sites of the patient.

8. The method according to any one of embodiments 1 to 5, wherein thetwo, separate injections of the aripiprazole IM depot formulation areadministered at separate deltoid injection sites of the patient.

9. The method according to any one of embodiments 1 to 8, wherein thepatient has schizophrenia.

10. The method according to any one of embodiments 1 to 8, wherein thepatient has bipolar I disorder.

11. The method according to any one of embodiments 1 to 10, wherein thesingle dose of oral aripiprazole ranges from about 2 mg to about 30 mgof aripiprazole.

12. The method according to embodiment 11, wherein the single dose oforal aripiprazole ranges from about 10 mg to about 30 mg.

13. The method according to embodiment 11, wherein the single dose oforal aripiprazole is 20 mg.

14. The method according to embodiment 11, wherein the single dose oforal aripiprazole is 10 mg.

15. The method according to embodiment 1, wherein when the patient is aCY2D6 poor metabolizer, each of the two, separate injections comprisesabout 300 mg of aripiprazole and the single dose of oral aripiprazole isabout 20 mg.

The present disclosure is directed to an alternative initiation regimenof two, separate administrations of an aripiprazole intramuscular (IM)depot formulation together with a shorter oral overlap. For example,simulations of an alternative initiation regimen of two 400 mginjections of an aripiprazole intramuscular (IM) depot formulation(e.g., Abilify Maintena®) at separate gluteal and/or deltoid injectionsites together with a single 20 mg dose of oral aripiprazole on thefirst day of treatment is shown to be sufficient and the alternativeinitiation regimen may be an additional option for initiation of, e.g.,Abilify Maintena®.

Aripiprazole is7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril.The empirical formula is C₂₃H₂₇Cl₂N₃O₂ and its molecular weight is448.38. The chemical structure is:

As used herein, reference to aripiprazole is to aripiprazole or a saltthereof, the crystalline form of aripiprazole or a salt thereof.Aripiprazole or a salt thereof may be in a monohydrate form(aripiprazole hydrate A) or in various anhydrous forms, which are knownto exist in the form of anhydrous crystal B, anhydrous crystal C,anhydrous crystal D, anhydrous crystal E, anhydrous crystal F, andanhydrous crystal G. All of these crystalline forms may be used asaripiprazole or a salt thereof in the injectable preparation of thepresent disclosure and further for example, aripiprazole is amonohydrate form.

A pharmaceutical composition comprising aripiprazole is known as anantipsychotic useful for the treatment of schizophrenia and bipolardisorder I.

Aripiprazole Traditional Dosing Regimen

The aripiprazole traditional dosing regimen includes a recommendedstarting and maintenance dose of Abilify Maintena® that is 300 mg or 400mg monthly (no sooner than 26 days after the previous injection). Forpatients who have never taken aripiprazole, the patient establishestolerability with oral aripiprazole prior to initiating treatment withAbilify Maintena®. Due to the half-life of oral aripiprazole, it maytake up to 2 weeks to fully assess tolerability.

After the first Abilify Maintena® injection, administer oralaripiprazole (10 mg to 20 mg) for 14 consecutive days to achievetherapeutic aripiprazole concentrations during initiation of therapy.For patients already stable on another oral antipsychotic (and known totolerate aripiprazole), after the first Abilify Maintena® injection,continue treatment with the antipsychotic for 14 consecutive days tomaintain therapeutic antipsychotic concentrations during initiation oftherapy.

If there are adverse reactions with the 400-mg dosage, one can considerreducing the dosage to 300 mg once monthly.

As such, the currently approved initiation regimen consists of a singleIM injection of aripiprazole intramuscular depot formulation togetherwith daily oral tablet administration of aripiprazole (10 to 20 mg) for14 consecutive days.

Reference herein to an aripiprazole intramuscular depot formulationrefers to Abilify Maintena® (aripiprazole), prescribing information forextended-release injectable suspension, for intramuscular use, initialUS approval: 2002, revised: 6/2020.

Aripiprazole Alternative Dosing Regimen

The present disclosure is directed to an alternative initiation regimenor dose initiation comprising administering two, separate about 100 mgto about 500 mg injections of aripiprazole intramuscular depotformulation (Abilify Maintena®) at separate gluteal and/or deltoidinjection sites together with a single oral aripiprazole dose on thefirst day of treatment. The single oral dose aripiprazole ranges fromabout 2 mg to about 30 mg; for example, the single oral dosearipiprazole ranges from about 10 mg to about 30 mg. This alternativeinitiation regimen provides an option for the first, or initiation, doseof aripiprazole intramuscular depot formulation. Maintenance dosingremains unchanged; for example, maintenance dose follows with singlemonthly injections thereafter of 400 mg or 300 mg of aripiprazole IMdepot formulation. As with the traditional dose initiation regimen, thealternative initiation regimen is applicable to both the deltoid andgluteal administration sites.

The present disclosure utilizes two, separate aripiprazole intramusculardepot formulation injections with a dose ranging from about 100 to about500 mg of aripiprazole. For example, the methods of the presentdisclosure administer two, separate 400 mg injections of an aripiprazoleintramuscular (IM) depot formulation to the patient at separate glutealand/or deltoid injection sites with administration occurring on a firstday of the treatment. In some embodiments, the two, separate injectionsof the aripiprazole IM depot formulation are administered at separategluteal injection sites or at separate deltoid sites of the patient. Ina further embodiment, the two, separate injections of the aripiprazoleIM depot formulation are administered at a gluteal and a deltoidinjection site of the patient. Further, the patient has schizophreniaand for example, the patient has bipolar I disorder.

The rationale for the selection of the alternative initiation regimendose is based on simulations from a population pharmacokinetic(s)(popPK) model. A range of dose initiation regimens were considered toshorten the length of oral dosing overlap with the first IM depotinjection while maintaining median concentrations within the previouslydefined therapeutic window and similar to those of the currentlyapproved dose initiation regimen (i.e., median, 25th to 75th, and 5th to95th percentile of concentration). Based on the results of thesimulations, the recommended dose for the alternative initiation regimenranges from about 100 mg to about 500 mg and in some embodiments, is,e.g., two 400 mg injections of the aripiprazole intramuscular depotformulation at separate gluteal and/or deltoid injection sites togetherwith a single dose of oral aripiprazole on the first day of treatment,for example, the single dose of oral aripiprazole ranges from about 2 mgto 30 mg of aripiprazole and for example, is a single 20 mg dose of oralaripiprazole.

Clinical Pharmacology Studies

The objective of the clinical pharmacology studies was to establish atwo-injection start regimen for the long-acting injectable aripiprazoleonce-monthly to obviate the need for 14-day oral aripiprazolesupplementation during treatment initial using a PK modeling andsimulation approach.

Methods

A previously developed popPK model (Food and Drug Administration: Centerfor Drug Evaluation and Research, Aripiprazole IM Depot Formulation:Clinical Pharmacology and Biopharmaceutics Review (Application No.202971s000) 2012)) which could adequately characterize aripiprazole PKfollowing oral administration and gluteal IM depot injections wasexpanded to include the deltoid site of injection. The final model wasdeveloped using PK data from 7 clinical trials following oraladministration and IM depot injections (both gluteal and deltoidmuscles). A total of 8,214 aripiprazole concentrations (16% oral, 65%gluteal, 16% deltoid, and 3% triceps or thigh administration) from 817subjects were included in the final analysis dataset. The predictiveperformance of the final model was assessed by prediction-correctedvisual predictive checks (pcVPCs).

The final popPK model was used to simulate and evaluate a range of doseinitiation regimens with shorter oral overlap following the first IMdepot injection to identify a regimen that: (1) remains within apreviously establish therapeutic window corresponding to the lower boundof the simulated median minimum aripiprazole concentrations at steadystate (Cmax,ss) following daily administration of 10 mg oralaripiprazole (94.0 ng/mL) and the 95^(th) percentile of maximumaripiprazole concentrations at steady state (Cmax,ss) following dailyadministration of the highest approved oral aripiprazole dose of 30 mg(741 ng/mL); and (2) results in plasma concentrations similar (i.e.,median, 25^(th) to 75^(th), and 5^(th) to 95^(th) percentile ofconcentration) to that of the currently approved one-injection startinitiation regimen (one 400 mg injection of aripiprazole once-monthlytogether with 14 days of oral aripiprazole [10 to 20 mg]).

A summary of the popPK modeling and simulation to support thealternative initiation regimen is provided, under “popPK Modeling”section header below. Simulations of aripiprazole plasma concentrationtime profiles following administration of the alternative initiationregimen to subjects without and with prior stabilization on oralaripiprazole (under “Alternative Initiation Regimen Without Prior OralAripiprazole Stabilization” and “Alternative Initiation Regimen WithPrior Oral Aripiprazole Stabilization” section headers below), toextensive or poor cytochrome P450 2D6 (CYP2D6) metabolizers (under“Subjects who are CYP2D6 Poor Metabolizers” section header below), andin scenarios following missed maintenance doses are also presented inthis module (under “Missed Maintenance IM Depot Dose” section headerbelow).

Aripiprazole Oral Formulation

Aripiprazole is a psychotropic drug that is available as an oral(aripiprazole) tablet. In some embodiments, oral tablets of aripiprazoleare available in, e.g., 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mgstrengths. Inactive ingredients in oral tablets, e.g., includecornstarch, hydroxypropyl cellulose, lactose monohydrate, magnesiumstearate, and microcrystalline cellulose. Colorants can include, e.g.,ferric oxide (yellow or red) and FD&C Blue No. 2 Aluminum Lake.

Aripiprazole is well absorbed after administration of a tablet, withpeak plasma concentrations occurring, e.g., within 3 hours to 5 hours;the absolute oral bioavailability of the tablet formulation is about87%. Oral tablets of aripiprazole can be administered with or withoutfood. For example, administration of a 15 mg oral tablet of aripiprazolewith a standard high-fat meal did not significantly affect the Cmax orAUC of aripiprazole or its active metabolite, dehydro-aripiprazole, butdelayed Tmax by 3 hours for aripiprazole and 12 hours fordehydro-aripiprazole.

Aripiprazole is metabolized primarily by three biotransformationpathways: dehydrogenation, hydroxylation, and N-dealkylation. Based onin vitro studies, CYP3A4 and CYP2D6 enzymes are responsible fordehydrogenation and hydroxylation of aripiprazole, and N-dealkylation iscatalyzed by CYP3A4. Aripiprazole is the predominant drug moiety in thesystemic circulation. At steady-state, dehydro-aripiprazole, the activemetabolite, represents about 40% of aripiprazole AUC in plasma.

Following a single oral dose of [14C]-labeled aripiprazole,approximately 25% and 55% of the administered radioactivity wasrecovered in the urine and feces, respectively. Less than 1% ofunchanged aripiprazole was excreted in the urine and approximately 18%of the oral dose was recovered unchanged in the feces.

The present disclosure utilizes an oral tablet of aripiprazole at asingle oral dose chosen from 2 mg to 30 mg, such as single oral doses of2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg of aripiprazole. In someembodiments, the single oral dose ranges from about 10 mg to about 30 mgof aripiprazole, such as about 20 mg of aripiprazole. In someembodiments, the single oral dose is chosen from 10 mg and 20 mg ofaripiprazole. In further embodiments, the single oral dose is 20 mg ofaripiprazole.

Aripiprazole Intramuscular Depot Formulation

In some embodiments, aripiprazole intramuscular depot formulationcomprises aripiprazole monohydrate; aripiprazole monohydrate is7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl] butoxy]-3,4dihydrocarbostyril monohydrate. The empirical formula isC₂₃H₂₇Cl₂N₃O₂H₂O and its molecular weight is 466.40. The chemicalstructure is:

For example, in some embodiments, aripiprazole intramuscular (IM) depotformulation is an extended-release injectable suspension in 400-mg or300-mg strength in pre-filled dual chamber syringes and 400-mg or 300-mgstrength vials. The labeled strengths are calculated based on theanhydrous form (aripiprazole). In some embodiments, inactive ingredients(per administered dose) for 400-mg and 300-mg strength products,respectively, include carboxymethyl cellulose sodium (16.64 mg and 12.48mg), mannitol (83.2 mg and 62.4 mg), sodium phosphate monobasicmonohydrate (1.48 mg and 1.11 mg) and sodium hydroxide (pH adjuster). Infurther embodiments, the extended-release injectable suspension in400-mg or 300-mg strength in pre-filled dual chamber syringes and 400-mgor 300-mg strength vials can be used to make dosage adjustments; thatis, in patents who are CYP2D6 poor metabolizers and in patents takingconcomitant CYP3A4 inhibitors or CYP2D6 inhibitors. Dosage adjustmentsfor 200 mg and 160 mg can be obtained by using the 300-mg or 400-mgstrength vials for intramuscular deltoid or gluteal injection forpatients taking CYP2D6 inhibitors, CYP3A4 inhibitors, or CYP3A4 forgreater than 14 days. The presently disclosed aripiprazole IM depotformulation, Ability Maintena®, for suspension in an extended-releaseform is described in U.S. Pat. Nos. 7,807,680, 8,030,313, 8,338,427,8,338,428, 8,399,469, 8,722,679, 8,759,351, 8,993,761, 9,089,567, and10,525,057; all of which are incorporated herein by reference in theirentirety.

In some embodiments, the activity of the aripiprazole intramusculardepot formulation is presumably primarily due to the parent drug,aripiprazole, and to a lesser extent, to its major metabolite,dehydro-aripiprazole, which has been shown to have affinities for D2receptors similar to the parent drug and represents about 29% of theparent drug exposure in plasma.

Aripiprazole absorption into the systemic circulation is slow andprolonged following intramuscular injection due to low solubility ofaripiprazole particles. Following a single-dose administration of thearipiprazole intramuscular depot formulation in the deltoid and glutealmuscle, the extent of absorption (AUCt, AUC∞) of aripiprazole wassimilar for both injection sites, but the rate of absorption (Cmax) was31% higher following administration to the deltoid compared to thegluteal site. However, at steady state, AUC and Cmax were similar forboth sites of injection. Following multiple intramuscular doses, theplasma concentrations of aripiprazole gradually rise to maximum plasmaconcentrations at a median Tmax of about 5-7 days for the gluteal muscleand about 4 days for the deltoid muscle. After gluteal administration,the mean apparent aripiprazole terminal elimination half-life was about29.9 days and about 46.5 days after multiple injections for every 4-weekinjection of the aripiprazole intramuscular depot formulation 300 mg and400 mg, respectively. Steady state concentrations for the typicalsubject were attained by the fourth dose for both sites ofadministration. Approximate dose-proportional increases in aripiprazoleand dehydro-aripiprazole exposure were observed after every four-week ofthe aripiprazole intramuscular depot formulation injections of 300 mgand 400 mg.

Elimination of aripiprazole is mainly through hepatic metabolisminvolving two P450 isozymes, CYP2D6 and CYP3A4. Aripiprazole is not asubstrate of CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, orCYP2E1 enzymes. Aripiprazole also does not undergo directglucuronidation.

The present disclosure utilizes two, separate aripiprazole intramusculardepot formulation injections with a dose ranging from about 100 mg toabout 500 mg of aripiprazole, and further for example, each of thetwo-aripiprazole intramuscular depot formulation injections comprise adose of 300 mg or 400 mg of aripiprazole. For example, the methods ofthe present disclosure administer two, separate 300 mg or 400 mginjections of an aripiprazole intramuscular (IM) depot formulation tothe patient at separate gluteal and/or deltoid injection sites withadministration occurring on a first day of the treatment. In someembodiments, the two, separate injections of the aripiprazole IM depotformulation are administered at separate gluteal injection sites or atseparate deltoid sites of the patient. In a further embodiment, the two,separate injections of the aripiprazole IM depot formulation areadministered at a gluteal and deltoid injection site of the patient.Further, the patient has schizophrenia and for example, the patient hasbipolar I disorder.

Examples

Therapeutic Window and Aripiprazole Plasma Concentrations During DoseInitiation with Alternative Initiation Regimen

The previously proposed therapeutic window corresponding to the lowerbound of the simulated median minimum aripiprazole concentrations atsteady state (Cmin,ss) following daily administration of 10 mg oralaripiprazole (94.0 ng/mL) and a conservative upper bound of thesimulated 75th percentile of maximum aripiprazole concentrations atsteady state (Cmax,ss) following daily administration of the highestapproved oral aripiprazole dose of 30 mg (534 ng/mL) is provided in FIG.10 . The statistics related to the simulations in this disclosure arepresented with median, 25th to 75th and 5th to 95th percentile ofconcentration. Thus, for head to head comparison of these simulationswith the previously proposed therapeutic window (FIG. 10 ), a horizontalreference line denoting the 95th percentile of the previously simulatedCmax,ss concentrations following daily administration of 30 mg oralaripiprazole (741 ng/mL) is added to simulations provided in thisdisclosure.

Based on simulations provided under the “Simulation Results” headerfound below, aripiprazole concentrations during dose initiation couldreach the 95th percentile of the previously simulated Cmax,ssconcentrations following daily administration of 30 mg oral aripiprazole(741 ng/mL), thus the following supportive information in lieu ofclinical data is provided:

-   -   Observed PK and safety data from a subset of subjects in this        trial with aripiprazole plasma concentrations that fell within        the 5th to 95th percentile of simulated concentrations following        administration of the proposed alternative initiation regimen        was evaluated and is provided under the “Comparison and Analyses        of Results Across Trials” header below. Overall, the safety        profile of these subjects was in accordance with the known        safety profile of Abilify Maintena®.    -   Aripiprazole concentrations exceeding both the 75th and 95th        percentile of simulated 30 mg oral Cmax,ss were observed and        well tolerated in a previously submitted phase 3 safety and        efficacy trial (clinicaltrials.gov identifier: NCT00705783,        entitled “Intramuscular Depot Formulation of Aripiprazole as        Maintenance Treatment in Patients with Schizophrenia        (ASPIRE).”). Plasma concentrations exceeding these levels during        dose initiation are highlighted in FIG. 13 . In FIG. 13 , SD        equals standard deviation.

Summary of Results of Individual Studies

A population PK analysis was conducted to expand the previouslysubmitted popPK model to incorporate the deltoid site of injection andperform simulations to examine predicted plasma concentrations followingadministration of the alternative initiation regimen at both deltoid andgluteal sites. A summary of the final combined popPK model is providedunder the “popPK” heading below. A summary of the results of a singleascending dose phase 1 trial to determine the PK, safety andtolerability following gluteal administration of a single high doseformulation of aripiprazole LAI that is provided under the “popPK”heading below.

popPK Modeling: Population Pharmacokinetic Analysis of AripiprazoleFollowing Oral Administration and Intra-Muscular Injection in theGluteal or Deltoid Muscle in Adult Subjects

A total of 8214 aripiprazole concentrations (16% oral, 65% gluteal, 16%deltoid, and 3% triceps or thigh administration) from 817 subjects wereincluded in a final combined analysis dataset. Pharmacokinetic dataincluded in this analysis consisted of data included from a previouspopPK report as well as aripiprazole concentrations following deltoid orgluteal injections from 2 additional trials conducted to supportaddition of the deltoid muscle as a site of administration.

The model was a 3-compartment model with sigmoid absorption for oraladministration (Ka), and 1st order absorption for IM (mainly gluteal)administration (IMKa).

The final combined model included the deltoid injection site into thepreviously developed model by adding a deltoid depot compartment with aseparate absorption rate constant (DKa) to the original model. Nofurther structural change or covariate analysis was conducted. A diagramof the structure of the final combined model is presented in FIG. 1 ,with updates to the original model to incorporate the deltoid site ofinjection shown in broken lines. In FIG. 1 , the following abbreviationsare used: CMT=compartment; DKa=deltoid IM 1st order absorption rateconstant; Frelative=relative bioavailability; IMKa=gluteal IM 1st orderabsorption rate constant; Ka=oral 1st order absorption rate constant;R1=rate of dose into oral absorption compartment; Vc=apparent centralvolume of distribution; Vp1=volume of distribution in Peripheralcompartment 1; Vp2=volume of distribution in Peripheral compartment 2;Q1=inter-compartmental clearance 1; Q2=inter-compartmental clearance 2.The final popPK model was a linear 3-compartment PK model, whichutilizes sigmoid absorption for oral administration and separate 1storder absorption for the gluteal and deltoid IM injections ofaripiprazole once-monthly.

All population PK parameters were fixed to the values estimated in theoriginal model for oral and gluteal administration except for DKa, whichwas estimated using data following deltoid administration. Theinter-individual variability (IIV) for the oral absorption rate constant(Ka) was fixed to the value estimated in the original model, while IIVfor clearance (CL), central volume of distribution (Vc), and the firstorder absorption rate constants following IM injections (IMKa and DKa)were estimated or re-estimated using the final combined analysisdataset.

It was assumed that the covariate effect remained the same as theoriginal model, and that the gender and body mass index (BMI) effect onIMKa, estimated from data following IM injection in gluteus maximusmainly, is also present for the deltoid injection. No additionalcovariate analysis was performed. Parameter definition and values of thefinal combined model are presented in Table 1 below:

TABLE 1 Parameter Estimates of the Final Combined Model RSE ShrinkageParameter Unit Definition Estimate % % R1 mg/hr Rate of dose into oral9.33 Fixed absorption compartment Ka 1/hr Oral 1st order 0.540 Fixedabsorption rate constant CL L/hr Apparent clearance for 3.71 Fixedsubjects who are not poor CYP2D6 metabolizers CLpm Lhr Apparentclearance for 1.88 Fixed subjects who are poor CYP2D6 metabolizersCL_INH2D6 — Proportional change in −0.511 Fixed CL in presence of astrong CYP2D6 inhibitor CL_INH3A4 — Proportional change in −0.237 FixedCL in presence of a strong CYP3A4 inhibitor Vc L Apparent central 93.4Fixed volume of distribution Q1 L/hr Inter-compartmental 0.591 Fixedclearance 1 Vp1 L Volume of distribution 118 Fixed in Peripheralcompartment 1 Q2 L/hr Inter-compartmental 28.8 Fixed clearance 2 Vp2 LVolume of distribution 134 Fixed in Peripheral compartment 2 IMKa 1/hrGluteal IM 1st order 0.000904 absorption safe Fixed constant DKa 1/hrDeltoid IM 1st order 0.000776  6.2% absorption rate constant IM Ka_BMI —Effect of BMI on IH Ka: −0.975 Fixed power for (BMI/28) IM Ka_male —Proportional shift of IM 0.346 Fixed Ka for males F relative — Relativesiosvallability 1.48 Fixed for IM Depot Radom Effect Inter-IndividualVariability (CV %) Ka — IIV on oral Ka 0.434 (65.9%) — 77% Fixed CL and— IIV on Apparent 0.153 (39.1%)  6.1%  8% CLpm clearance for allsubjects Vc — IIV on Vc 2.18 (148%).  2.5% 44% IMKa — IIV on gluteal IMKa 0.359 (60.0%)  7.7% 24% DKa — IIV on deltoid IM Ka 0.237 (48.9%)24.4% 74% Residual Variability (% CV) Phase 1 — Proportional residual0.0693 (26.3%) — — error for phase 1 data Phase 3 — Proportionalresidual 0.0600 (24.5%) — — error for phase 3 data Minimum Value ofObjective Function: 64759

From Table 1, it is noted that % CV is the percent coefficient ofvariation and RSE is standard error relative to the mean.

The predictive performance of the final combined model was assessed byprediction-corrected visual predictive checks (pcVPCs). The pcVPCs ofthe final combined population PK model for deltoid and gluteal sites ofadministration following the first and the fifth monthly administrationsare presented in FIGS. 2A-2D. In FIGS. 2A-2D, the followingabbreviations are used: CI confidence interval; and the visualpredictive check following the 1st gluteal injection includes PK datafrom subjects coadministered with oral aripiprazole. Overall, the pcVPCsshowed good predictive performance of the final combined model for thedeltoid and gluteal sites of administration as the distributions of theobserved data are comparable with the 5th to 95th percentile ofconcentrations of the model-based simulation. Overall, pcVPCs confirmedthe variability seen in the observed PK data could be adequatelydescribed by the final popPK model, as the distributions of the observeddata are comparable with the 90% prediction intervals of the model-basedsimulation following single and multiple administrations in the deltoidand gluteal sites.

Simulation Results

The final combined model was utilized to simulate aripiprazole plasmaconcentration-time profiles following oral, gluteal, and/or deltoidadministration of aripiprazole. To compare simulated PK profiles, avirtual population consisting of 817 subjects with similar demographiccharacteristics to the subjects enrolled in the clinical trials in thefinal analysis dataset (provided under “popPK Model”) was used to ensureonly the dosing regimen changed across simulations. Individual PKparameters for subjects in the final analysis dataset (all assigned asCYP2D6 extensive metabolizers (EM) except for simulation of CYP2D6 poormetabolizers [PM] subjects) were generated from the final combined PKmodel and its final parameter estimates. Individual PK profilesfollowing oral, gluteal, and deltoid administration of aripiprazole weresimulated using a 2-hour sampling interval for 24 hours post thepreceding oral dose and every 24-hour sampling post the preceding IMDepot dose. A full listing of all simulations performed is provided inFIGS. 3A-3C.

Alternative Initiation Regimen Without Prior Oral AripiprazoleStabilization

Several scenarios for dose initiation were simulated to assess the timeto achieve concentrations within the therapeutic window as providedabove under the heading entitled “Therapeutic Window and AripiprazolePlasma Concentrations During Dose Initiation with Alternative InitiationRegimen.” The median and 5th to 95th percentile of concentration ofsimulated aripiprazole plasma PK profiles for the currently approvedinitiation regimen (400 mg with 14 days of 10 to 20 mg oral dosing) andthe alternative initiation regimen (2×400 mg with 1 day of 20 mg oraldosing) administered as two separate injections in the gluteal and/ordeltoid sites are shown in FIGS. 4A-4D. In FIGS. 4A-4D, approvedinitiation regimen was 10 to 20 mg oral (14 days) and 400 mg IM depot(day 1).

Based on the simulations, in FIGS. 4A-4D, the median and 5th to 95thpercentile of concentration of the aripiprazole PK profile followingadministration of the proposed alternative initiation regimen iscomparable to the approved initiation regimen of 400 mg aripiprazole IMon Day 1+10 mg to 20 mg oral aripiprazole for 14 days, for example:

-   -   Median aripiprazole PK profiles following the alternative        initiation regimen reach therapeutic levels (10 mg daily        aripiprazole Cmin,ss of 94.0 ng/mL) on the first day and remain        above the lower threshold of the therapeutic window thereafter.    -   The 95th percentile of simulated concentrations following the        proposed alternative initiation regimen are comparable to, or        lower than, the 95th percentile of the currently approved        regimen and within the upper bound of the therapeutic window, as        discussed above.    -   Plasma concentrations for all regimens exceed the previously        used conservative upper bound of the 75th percentile of        simulated Cmax,ss following daily administration of 541 ng/mL        but remain below the 95th percentile of the simulated 30 mg oral        Cmax,ss (741 ng/mL).    -   The alternative initiation regimen has no impact on steady state        maintenance concentration.

Alternative Initiation Regimen With Prior Oral AripiprazoleStabilization

In the approved label for Abilify Maintena®, the first dose isadministered with concomitant oral aripiprazole (10 to 20 mg) for 14consecutive days to adult patients stabilized with oral aripiprazole.Thus, simulations were performed to predict and compare plasmaconcentrations during the 28 days following administration of thecurrently approved and the alternative initiation regimen to patientsstabilized with 20 mg aripiprazole, which is the highest typical oraldose a patient would be receiving prior to initiating treatment with IMdepot of aripirazole. The median, 5th, 25th to 75th, and 95th percentileof simulated aripiprazole plasma PK profiles for the currently approvedand the alternative initiation regimen administered as two separateinjections in the gluteal or deltoid sites of subjects with priorstabilization on an oral aripiprazole dose of 20 mg are presented inFIGS. 5A and 5B. In FIGS. 5A and 5B, the approved initiation regimen was10 to 20 mg oral (14 days) and 400 mg IM depot (Day 1). The startingconcentration at time zero is the average concentration at steady statefor subjects stabilized on 20 mg oral aripiprazole.

Based on the simulations, the median and 5th to 95th percentile ofconcentration of the aripiprazole PK profile following administration ofthe alternative initiation regimen is comparable to the approvedinitiation regimen when administered to subjects already stabilized on20 mg oral aripiprazole:

-   -   The 95th percentile of simulated concentrations following the        alternative initiation regimen are comparable to, or lower than,        the 95th percentile of the approved regimen.    -   The alternative initiation regimen has no impact on steady state        maintenance concentration.

Subjects who are CYP2D6 Poor Metabolizers

In subjects who are known to be cytochrome P450 2D6 poor metabolizers(CYP2D6 PM), the currently approved IM depot initiation dose should bereduced from 400 to 300 mg due to an approximately 50% lower apparentclearance of aripiprazole. Simulations were thus performed to predictaripiprazole concentrations following administration of the alternativeinitiation regimen to CYP2D6 extensive metabolizers (EM) and PMsubjects. A comparison of the simulated median concentration timeprofiles and boxplots of maximum aripiprazole plasma concentrations(Cmax) following a single dose of 20 mg oral aripiprazole along with twoadministrations of either 400 mg (CYP2D6 EM and PM subjects) or 300 mg(only CYP2D6 PM subjects) Abilify Maintena® in the gluteal or deltoidsites is presented in FIGS. 6A and 6B. In FIGS. 6A and 6B, the approvedinitiation regimen was 10 to 20 mg oral (14 days) and 400 mg IM depot(Day 1).

Simulations of plasma concentrations were performed to also allowcomparison of the simulated median concentration time profiles andboxplots of aripiprazole Cmax following a single dose of 20 mg oralaripiprazole along with two administrations of either 400 mg (CYP2D6 EMand PM subjects) or 300 mg (CYP2D6 PM subjects only) IM depotaripiprazole formulation in the gluteal or deltoid sites of subjects orpatients with prior stabilization on 20 mg (EM) or 10 mg (PM) oralaripiprazole. These simulations are presented in FIGS. 7A and 7B. InFIGS. 7A and 7B, the approved initiation regimen is 10 to 20 mg oral (14days)+400 mg IM depot (Day 1). The starting concentration at time zerois the average concentration at steady state for CYP2D6 EM stabilized on20 mg oral aripiprazole and PM subjects stabilized on 10 mg oralaripiprazole. For PMs, prior oral dose was reduced by half (10 mginstead of 20 mg).

As expected, simulations resulted in CYP2D6 PM subjects exhibitinghigher aripiprazole Cmax and exposure compared to CYP2D6 EM subjectswhen both receive two administrations of 400 mg IM depot aripiprazoleformulation. Thus, a dose reduction of the proposed regimen from two 400mg IM depot aripiprazole formulation administrations to two 300 mg IMdepot aripiprazole formulation administrations along with a single doseof 20 mg oral aripiprazole is recommended for known CYP2D6 PM subjectsor patients to ensure concentrations following the alternativeinitiation regimen are comparable to the currently approved regimen andremain within or slightly above the therapeutic window.

Missed Maintenance IM Depot Dose

Simulations were performed to assess aripiprazole concentrationsfollowing a missed second, third, fourth, or steady-state dose of IMdepot aripiprazole formulation to determine whether the alternativeinitiation regimen could be applicable to situations when the currentlyapproved initiation regimen requires concurrent oral administration ofaripiprazole for 2 weeks with a single IM depot aripiprazole formulationinjection.

A comparison of the simulated median aripiprazole plasma concentrationsfollowing administration of the alternative initiation regimen or thecurrently approved initiation regimen in the gluteal or deltoid sitewhen the second or third IM depot aripiprazole formulation dose isadministered 5 weeks after the previous injection are provided in FIGS.8A-8D. In FIGS. 8A-8D, the approved initiation regimen was 10 to 20 mgoral (14 days) and 400 mg IM depot (Day 1).

A comparison of the simulated median aripiprazole plasma concentrationsfollowing administration of the alternative initiation regimen or thecurrently approved initiation regimen in the gluteal or deltoid sitewhen the 4th or 5th (steady-state) dose is administered 6 weeks afterthe previous injection are provided in FIGS. 9A-9D. In FIGS. 9A-9D, theapproved initiation regimen was 10 to 20 mg oral (14 days) and 400 mg IMdepot (Day 1).

In all simulations, administration of the alternative initiation regimenfollowing a missed maintenance IM depot resulted in median aripiprazoleconcentrations above the lower threshold of the therapeutic window andsimilar to those following the approved initiation regimen.

Based on the results of the simulations, the alternative initiationregimen may be administered in place of concomitant oral aripiprazolefor 14 days together with a single IM depot formulation of aripiprazoleinjection on Day 1 when a maintenance IM depot dose is missed. Such atreatment strategy following a missed dose is consistent with that inthe Abilify Maintena® label.

Comparison and Analyses of Results Across Trials

An analysis was performed to evaluate observed safety outcomes from asubset of 17 subjects from the phase I clinical trial describe belowwith plasma concentration time profiles that fall within the 5th to 95thpercentile of simulated concentrations following administration of thealternative initiation regimen and are consistently above the mean PKprofile following a single gluteal administration of 400 mg AbilifyMaintena®. A graphical comparison of all aripiprazole concentration timeprofiles following a single dose of 780 mg (N=18) or 1200 mg (N=13)aripiprazole LAI to the gluteal muscle (from a previous clinical trial),with aripiprazole concentration time profiles from the subset of 17subjects highlighted in red, is presented in FIG. 11 . In FIG. 11 , theN equals the number of subjects; the subset of 17 subjects from a trialwith plasma concentration time profiles that fall within the 5th to 95thpercentile of simulated concentration following administration of thealternative initiation regimen and are consistently above the mean PKprofile following a single gluteal administration of 400 mg AbilifyMaintena®; and lower limit of quantitation of aripiprazole was 0.500ng/mL.

For reference, the mean (i.e., the lower dark horizontal line)aripiprazole plasma concentration time profile following administrationof a single dose of 400 mg Abilify Maintena® to the gluteal muscle andthe 5th to 95th percentile of simulated concentrations (final combinedmodel) following administration of the alternative initiation regimen(20 mg oral [Day 1]+2×400 mg aripiprazole IM depot formulation [Day 1])to the gluteal site (shaded area) are also presented.

Of the 17 subjects identified, 7 subjects were treated with 1200 mgaripiprazole LAI and 10 subjects were treated with 780 mg aripiprazoleLAI. A review of the safety data from these subjects did not identifyany unexpected AEs and it was concluded that their safety profile was inaccordance with the known safety profile of Abilify Maintena®.

CONCLUSIONS

Simulations indicated that the two-injection start regimen of twoadministrations of aripiprazole once-monthly at separate gluteal and/ordeltoid injection sites with a single 20 mg dose of oral aripiprazole onthe first day of treatment regimen would: (1) achieve therapeuticaripiprazole plasma concentrations on the first day of treatment; (2)support consistent clinical effectiveness over the entire dosinginterval; (3) result in comparable aripiprazole plasma concentrationsthus, safety profile, to the currently approved (traditional) initiationregimen; and (4) provide a new initiation option which obviates the needfor the 14-day oral tablet supplementation, potentially reducingcompliance related undertreatment during the initiation phase oftreatment.

A Phase 1, Open Label, Single Ascending Dose, Parallel Arm Trial toDetermine the Pharmacokinetics, Safety, and Tolerability of Aripiprazole2 Month Intramuscular Depot Administered Gluteally in Adult Subjectswith Schizophrenia

This trial was an open-label, single ascending dose, parallel-arm,multiple-center trial to determine the PK, safety, and tolerability ofsingle-dose administration of 780 mg (Cohort 1) and 1200 mg (Cohort 2)of a high dose formulation of aripiprazole LAI that is in the glutealmuscle of adult subjects with schizophrenia. Data from this trial issupportive information, as it was evaluated for instances in whicharipiprazole plasma concentrations increased at a similar rate andreached levels predicted in simulations for the alternative initiationregimen. Overall, aripiprazole LAI was well tolerated when administeredIM as a single dose of 780 mg and 1200 mg to adult subjects withschizophrenia. In a subset of 17 subjects, the administration ofaripiprazole LAI resulted in higher aripiprazole plasma concentrationsas well as faster absorption rates, resulting in aripiprazole plasmaconcentration time profiles that fell within the 5th to 95th percentileof simulated concentrations following administration of the proposedalternative initiation regimen and were consistently above the mean PKprofile following a single gluteal administration of 400 mg AbilifyMaintena® (FIG. 1 ). Safety data from this subset of subjects wasevaluated and compared to the known safety profile of Abilify Maintena®.Further details of this analysis are provided under the section entitled“Comparison and Analyses of Results Across Trials.”

The aripiprazole LAI was an extended release presentation for dosingevery 2 months at the dose levels evaluated. The extension of the dosinginterval for the aripiprazole LAI was primarily through an increase inthe dose while maintaining minimum aripiprazole concentrations that arecomparable to Abilify Maintena® after multiple doses. The aripiprazoleLAI was engineered with higher aripiprazole concentrations in the drugproduct (300 mg/mL vs 200 mg/mL) and minor changes to the vehiclecompared to currently marketed/approved Abilify Maintena®. The meanaripiprazole particle size distribution and the dissolution profile forthe aripiprazole LAI formulation were comparable with the AbilifyMaintena® formulation and the formulation was expected to have a similarextended release profile compared with the approved Abilify Maintena®formulation. Mean (standard deviation [SD]) aripiprazole plasmaconcentration time profiles following administration of a single dose of780 mg or 1200 mg aripiprazole to the gluteal muscle in subjects withschizophrenia are presented in FIG. 12 .

A summary of the aripiprazole PK parameters following single-doseadministration of a single dose of 780 mg or 1200 mg aripiprazole to thegluteal muscle in subjects with schizophrenia is presented in Table 2below.

TABLE 2 Mean (SD) Aripiprazole Pharmacokinetic Parameters FollowingAdministration of a Single Dose of 780 mg or 1200 mg Aripiprazole LongActing Injectable to the Gulteal Muscle of Subjects with SchizophreniaAripiprazole Aripiprazole 2M RTU 2M RTU LAI LAI 780 mg 1200 mg PKParameter (N = 18) (N = 13) Cmax (ng/mL) 271 (157) 391 (200)tmax(day)^(a) 25.1 (4.07-76.0) 41.0 (6.09-61.9) AUCt (ng · day/mL) 12600(3710) 23800 (7620) AUC∞ (ng · day/mL) 13400 (4600)^(b) 24700 (8080)^(c)t½ (day) 22.1 (16.5)^(b) 20.0 (9.2)^(c) CL/F (mL/day/kg) 763 (299)^(b)596 (207)^(c) Cmax/Dose (ng/mL/mg) 0.347 (0.201) 0.326 (0.167) AUCt/Dose([ng · day/mL]/mg) 16.1 (4.75) 19.8 (6.35) AUC∞/Dose([ng · day/mL]/mg)17.2 (5.90)^(b) 20.6 (6.73)^(c)

From Table 2, it is noted that AUC∞ is area under the concentration-timecurve calculated from time zero to infinity; AUCt is area under theconcentration-time curve calculated to the last observable concentrationat time t; CL/F is apparent clearance of drug from plasma afterextravascular administration; RTU is ready to use; tmax is time tomaximum (peak) plasma concentration; t1/2 is elimination half-life.Additionally, ^(a)Median (minimum-maximum); ^(b)n=14; and ^(c)n=11.

Conclusions from this data include, for example:

-   -   Aripiprazole LAI was well tolerated when administered IM as a        single dose of 780 and 1200 mg to adult subjects with        schizophrenia.    -   Single-dose administration of 780 or 1200 mg aripiprazole LAI to        the gluteal muscle resulted in, respectively, a 100% and 200%        increase in aripiprazole Cmax and exposure (area under the        concentration-time curve [AUC] calculated from time zero to        infinity [AUC∞] and AUC calculated to the last observable        concentration at time t [AUCt]) than previously observed        following single-dose administration of 400 mg Abilify Maintena®        to the gluteal muscle.    -   Single-dose administration of 780 or 1200 mg aripiprazole LAI to        the gluteal muscle resulted in a slightly less than proportional        increase in aripiprazole Cmax and a slightly more than dose        proportional increase in exposure (AUCt and AUC∞) based on mean        values corrected for dose.    -   Administration of 780 mg aripiprazole LAI to the gluteal muscle        resulted in shorter median time to maximum (peak) plasma        concentration (tmax) values for aripiprazole (25.1 days vs 41.0        days) when compared to the 1200 mg dose.    -   Following administration of 780 or 1200 mg aripiprazole LAI to        the gluteal muscle, mean terminal elimination half-life (t1/2)        values for aripiprazole (22.1 and 20.0 days, respectively) were        comparable, and similar to the median t1/2 following single-dose        administration of 400 mg Abilify Maintena® to the gluteal muscle        (24.0 days).    -   A consistent increase in aripiprazole concentrations followed by        a decline and a secondary peak in concentrations were observed        following administration of 780 or 1200 mg aripiprazole LAI to        the gluteal muscle based on examination of mean, median, and        individual concentration-time profiles.    -   Additionally, this Phase I trial supports the use of the present        disclosure of a method of dose initiation for an aripiprazole        treatment to a patient in need thereof comprising: administering        two, separate injections of an aripiprazole intramuscular (IM)        depot formulation ranging from about 10 mg to about 500 mg of        aripiprazole to the patient at separate gluteal and/or deltoid        injection sites, and a single dose of oral aripiprazole, wherein        administration occurs on a first day of the treatment. That is,        the use of two injections ranging from about 10 mg to about 500        mg of aripiprazole did not result in any unexpected AEs and the        safety profile was in accordance with the known safety profile        of Ability Maintena®.

All publications and patents mentioned herein are hereby incorporated byreference in their entirety as if each individual publication or patentwas specifically and individually indicated to be incorporated byreference.

Claims or descriptions that include “or” or “and/or” between at leastone members of a group are considered satisfied if one, more than one,or all of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The disclosure includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Thedisclosure includes embodiments in which more than one, or all the groupmembers are present in, employed in, or otherwise relevant to a givenproduct or process.

Furthermore, the disclosure encompasses all variations, combinations,and permutations in which at least one limitation, element, clause, anddescriptive term from at least one of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include at least one limitation found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should be understood that, in general, where the disclosure,or aspects of the disclosure, is/are referred to as comprisingparticular elements and/or features, embodiments of the disclosure oraspects of the disclosure consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. Where rangesare given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub range within the stated ranges indifferent embodiments of the disclosure, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

Those of ordinary skill in the art will recognize or be able toascertain using no more than routine experimentation, many equivalentsto the specific embodiments of the disclosure described herein. Suchequivalents are intended to be encompassed by the following claims.

1-15. (canceled)
 16. A method of dose initiation for an aripiprazoletreatment to a patient in need thereof comprising: administering two,separate injections of an aripiprazole intramuscular (IM) depotformulation, wherein each injection comprises from about 10 mg to about500 mg of aripiprazole, to the patient at an injection site chosen froma gluteal site, a deltoid site, and combinations thereof, and a singledose of oral aripiprazole, wherein the step of administering occurs on afirst day of the treatment.
 17. The method according to claim 16,wherein each of the two, separate injections comprise 400 mg ofaripiprazole.
 18. The method according to claim 16, further comprisingafter the first day of treatment, administering a single monthly,maintenance injection of the aripiprazole IM depot formulation.
 19. Themethod according to claim 18, wherein the single monthly, maintenanceinjection is chosen from about 300 mg and about 400 mg of aripiprazolein the aripiprazole IM depot formulation.
 20. The method according toclaim 18, wherein when the patient is a CYP2D6 poor metabolizer or istaking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors for greaterthan 14 days, the single monthly, maintenance injection is chosen from160 mg and 200 mg of aripiprazole in the aripiprazole IM depotformulation.
 21. The method according to claim 16, wherein the two,separate injections of the aripiprazole IM depot formulation areadministered at separate gluteal injection sites of the patient.
 22. Themethod according to claim 16, wherein the two, separate injections ofthe aripiprazole IM depot formulation are administered at gluteal anddeltoid injection sites of the patient.
 23. The method according toclaim 16, wherein the two, separate injections of the aripiprazole IMdepot formulation are administered at separate deltoid injection sitesof the patient.
 24. The method according to claim 16, wherein thepatient has schizophrenia.
 25. The method according to claim 16, whereinthe patient has bipolar I disorder.
 26. The method according to claim16, wherein the single dose of oral aripiprazole ranges from about 2 mgto about 30 mg of aripiprazole.
 27. The method according to claim 26,wherein the single dose of oral aripiprazole ranges from about 10 mg toabout 30 mg.
 28. The method according to claim 26, wherein the singledose of oral aripiprazole is 20 mg.
 29. The method according to claim26, wherein the single dose of oral aripiprazole is 10 mg.
 30. Themethod according to claim 16, wherein when the patient is a CY2D6 poormetabolizer, each of the two, separate injections comprises about 300 mgof aripiprazole and the single dose of oral aripiprazole is about 20 mg.